Agonistic antibodies to TrkC receptors and uses thereof

Abstract

There are provided herein novel monoclonal antibodies that selectively bind and/or activate TrkC receptors, pharmaceutical compositions thereof and the use thereof for treating or preventing conditions which require activation of TrkC, such as amyotrophic lateral sclerosis and other neurodegenerative conditions and motor neuron diseases. The monoclonal antibodies are useful to screen for agents that share the same binding epitope on the TrkC receptor.

What is claimed is: 
     
       1. A monoclonal antibody that is produced from the hybridoma deposited with the International Depositary Authority of Canada on May 26, 2010 and having accession no. 090310-02, or from a progenitor cell thereof; or, a fragment, portion, variant or derivative thereof, said fragment, portion, variant and derivative thereof comprising all of the 6 CDRs from the monoclonal antibody produced by the hybridoma having accession no. 090310-02. 
     
     
       2. The monoclonal antibody of  claim 1 , wherein said antibody does not bind the D5 domain of TrkC. 
     
     
       3. The monoclonal antibody or the fragment, portion, variant or derivative of  claim 1 , wherein the antibody or fragment, portion, variant or derivative activates TrkC. 
     
     
       4. The monoclonal antibody or the fragment, portion, variant or derivative of  claim 1 , wherein the antibody or the fragment, portion, variant or derivative thereof binds and/or activates human TrkC. 
     
     
       5. The monoclonal antibody or the fragment, portion, variant or derivative of  claim 1 , wherein the antibody or the fragment, portion, variant or derivative thereof binds and/or activates murine or rat TrkC and/or wherein the antibody or the fragment, portion, variant or derivative thereof does not bind and/or activate TrkA, TrkB and/or p75NTR and/or wherein the antibody or the fragment, portion, variant or derivative thereof binds and/or activates TrkC differently from NT-3 and/or wherein the antibody or the fragment, portion, variant or derivative thereof specifically binds an epitope of human TrkC with a sequence comprising the juxtamembrane region or a portion thereof of human TrkC. 
     
     
       6. A pharmaceutical composition comprising the monoclonal antibody or the fragment, portion, variant or derivative of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       7. A method of activating TrkC in a subject, comprising administering a therapeutically effective amount of the monoclonal antibody or the fragment, portion, variant or derivative of  claim 1  to the subject, such that TrkC is activated in the subject. 
     
     
       8. The method of  claim 7 , wherein the subject is a human and the TrkC is human TrkC. 
     
     
       9. The method of  claim 8 , wherein the monoclonal antibody or the fragment, portion, variant or derivative is administered in combination with a second therapeutic agent. 
     
     
       10. The method of  claim 9 , wherein the second therapeutic agent is selected from a muscle relaxant, a tranquilizer, an anticonvulsant, a nonsteroidal anti-inflammatory agent, a benzodiazepine, riluzole and amitriptyline. 
     
     
       11. The method of  claim 7 , wherein the subject suffers from: a neurological or neurodegenerative condition; a motor neuron disease which requires activation of TrkC; a stroke; a spinal cord injury; an axotomy; or amyotrophic lateral sclerosis (ALS); or the subject has been injured by a wound, surgery, ischemia, infection, a metabolic disease, malnutrition, a malignant tumor or a toxic drug. 
     
     
       12. The method of  claim 11 , wherein the subject has a motor neuron disease selected from the group consisting of ALS, progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, progressive muscular atrophy, spinal muscular atrophy, SMA Type I, SMA type II, SMA type III, Fazio-Londe disease, Kennedy disease, congenital SMA with arthrogryposis, and post-polio syndrome. 
     
     
       13. The method of  claim 7 , wherein the monoclonal antibody or the fragment, portion, variant or derivative is administered to the subject parenterally, intravenously, subcutaneously or interperitoneally. 
     
     
       14. A method for treating ALS in a subject, comprising administering a therapeutically effective amount of the monoclonal antibody or the fragment, portion, variant or derivative of  claim 1  to the subject. 
     
     
       15. A method for treating or preventing a neurodegenerative condition or for treating a motor neuron disease in a subject, comprising administering a therapeutically effective amount of the monoclonal antibody or the fragment, portion, variant or derivative of  claim 1  to the subject. 
     
     
       16. The monoclonal antibody or fragment, portion, variant or derivative of  claim 1 , comprising a single-chain antibody and/or a Fab fragment. 
     
     
       17. An antigen-binding fragment of the monoclonal antibody of  claim 1  which specifically binds and/or activates TrkC receptor, said antigen-binding fragment comprising all of the 6 CDRs from the monoclonal antibody produced by the hybridoma haying accession no. 090310-02. 
     
     
       18. The monoclonal antibody or the fragment, portion, variant or derivative of  claim 1 , wherein the antibody, fragment, portion, variant or derivative is humanized, veneered or chimeric. 
     
     
       19. A method of in vitro screening for an agent which binds to TrkC receptor and can thereby affect TrkC receptor biological activity, which comprises:
 combining the antibody or the fragment, portion, variant or derivative of  claim 1  with TrkC receptor, in the presence or absence of a candidate agent; and 
 determining whether binding of said antibody to TrkC receptor is reduced in the presence of the candidate agent; 
 wherein a reduction in antibody binding indicates that said candidate agent binds to TrkC receptor, and can thereby affect TrkC receptor biological activity. 
 
     
     
       20. A hybridoma deposited with the International Depositary Authority of Canada on May 26, 2010 and having accession no. 090310-02 or a progenitor cell thereof.